bims-conane 2025-11-02 papers

J Biol Chem. 2025 Oct 27. pii: S0021-9258(25)02715-2. [Epub ahead of print] 110863

The histone methyltransferase MLL1 complex inhibits expression of fetal hemoglobin.

Yufen Han, Bjorg Gudmundsdottir, Kristbjorn O Gudmundsson, Kartik R Roy, John Tisdale, Yang Du.

Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. Moreover, treatment of CD34+ HSPCs from SCD patients with MENIN inhibitors substantially increased γ-globin expression in their erythroid progenies. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and β-thalassemia.

Keywords: Men1; chromatin regulation; differentiation; hemoglobin; transcription regulation

DOI: https://doi.org/10.1016/j.jbc.2025.110863

Br J Haematol. 2025 Oct 26.

Achieving clinically meaningful changes in haemoglobin levels in patients with non-transfusion-dependent β-thalassaemia treated with luspatercept: A post hoc analysis of the phase 2 BEYOND trial.

Khaled M Musallam, Ali T Taher, John B Porter, Antonis Kattamis, Mrudula B Glassberg, Luciana Moro Bueno, Patricia Martin-Regueira, Marta Reverte, Loyse Felber Medlin, Matthew Dyer, Kefeng Wang, Maria Domenica Cappellini.

In this post hoc analysis of the phase 2 BEYOND trial, the majority of patients with non-transfusion-dependent β-thalassaemia achieved clinically meaningful haemoglobin levels ≥10.0 g/dL and increases from baseline ≥1.0 g/dL, thresholds associated with reduced risk of morbidity and mortality and recommended as an indication and target for treatment by international management guidelines, respectively.

Keywords: anaemia; clinical trials; haemoglobin; β‐thalassaemia

DOI: https://doi.org/10.1111/bjh.70227

J Hum Genet. 2025 Oct 31.

Gardos channelopathies: novel insights into KCNN4 mutations and their clinical impact.

Prashant Warang, Pradnya Dehadrai, Neha Samanpalliwar, Rashmi Dongerdiye, Tejashree Anil More, Ashish Chiddarwar, Pallavi Thaker, Prachi Kamble, Arati Saptarshi, Manisha Madkaikar, Prabhakar S Kedar.

Gardos channelopathies are rare hereditary hemolytic anaemias caused by mutations in the KCNN4 gene, which encodes the calcium-activated potassium channel (KCa3.1) in red blood cells. In this study, we report three unrelated Indian patients with unexplained chronic hemolytic anaemia. Whole exome sequencing revealed distinct KCNN4 mutations: a homozygous c.5G > A mutation (p.Gly2Asp) in Case I, a compound heterozygous condition with the Hb Nottingham mutation (HBB: c.296T > G) and a splice-site mutation in KCNN4 (c.931-1G > C) in Case II, and homozygous c.541A > T mutation (p.Ser181Cys) in Case III. All three patients presented with chronic anaemia, indirect hyperbilirubinemia, reticulocytosis, and recurrent blood transfusions. Red cell enzyme studies (G6PD, PK, GPI) showed normal activities, and flow cytometry-based EMA binding was normal. Haemoglobin electrophoresis by HPLC was normal, except in Case II, and tested positive for unstable haemoglobin using a heat instability test. Flow cytometry revealed significantly elevated intracellular calcium levels and reactive oxygen species (ROS) in all cases, indicating oxidative stress under osmotic stress. In Case III, a Percoll density gradient assay demonstrated dehydrated erythrocytes, supporting the diagnosis. This study expands the mutation spectrum of Genetic diagnosis using NGS, which is essential for appropriate clinical management and genetic counselling in unexplained cases of hemolytic anaemia. Elevated intracellular calcium levels play a key role in hemolysis, suggesting that calcium-modulating therapies could aldehyleviate symptoms.

DOI: https://doi.org/10.1038/s10038-025-01414-1

EMBO Rep. 2025 Oct 30.

Stage-specific TRIM10 expression regulates erythroid maturation.

Heesoo Kim, Wonji Shin, Dongeun Lee, Byunghoon Jeon, Yongbo Kim, Donghyuk Shin, Hyobin Jeong, Jun Young Hong, Sungwook Lee, Boyoun Park.

Mammalian erythroid cells undergo extensive organelle and protein remodeling during erythropoiesis. The transcriptome and proteome of ubiquitin E3 ligases change dynamically during erythroid differentiation, yet mechanisms beyond E3 activity remain unclear. Here, we identify that tripartite motif-containing protein 10α (TRIM10α), an erythroid- and stage-specific E3 ligase, as crucial for stepwise erythroid maturation. TRIM10α self-association to localize on erythroblast surfaces, binding extracellular complement C1q, which facilitates pyrenocyte encapsulation and macrophage recognition. Surface C1q interacts with EpoR to promote lysosomal degradation, and its depletion prolongs Epo signaling. Notably, cytosolic TRIM10α enhances hemoglobin (Hb) maturation and sequesters Hb aggregates under oxidative conditions. Ultimately, TRIM10α self-ubiquitination and its binding to p62 are anticipated to lead to TRIM10α degradation, promoting the removal of Hb aggregates via autophagy. In contrast to TRIM10α, an alternatively spliced TRIM10β, which is barely expressed in human tissues and cells, forms deleterious aggregates, suggesting that evolutionary suppression of TRIM10β supports erythroid homeostasis. Our findings propose that aberrant TRIM10 expression drives erythroid-related diseases and highlight TRIM10 as a potential biomarker or therapeutic target.

Keywords: C1q; Erythropoiesis; Hemoglobin Maturation; TRIM10

DOI: https://doi.org/10.1038/s44319-025-00616-0